本文選題：感音神經(jīng)性聾 + 鼻咽癌��； 參考：《復(fù)旦大學(xué)》2012年博士論文

【摘要】：一鼻咽癌IMRT技術(shù)下放化療患者放射性內(nèi)耳損傷臨床分析 背景和目的 我國是鼻咽癌高發(fā)國,放射治療是目前最有效的治療手段,同時,放射治療也是其他頭頸部惡性腫瘤的主要治療方式之一[1]。近年來,頭頸部腫瘤治療后五年生存率有了明顯提高,但隨之而來的遠(yuǎn)期副反應(yīng)也越來越被認(rèn)識,其中放射性耳病發(fā)病率居晚期并發(fā)癥的第二位[2]。放療后感音神經(jīng)性聾(Sensori-neural hearing loss,SNHL)是鼻咽癌放射治療后的常見后遺癥,尤其是聯(lián)合化療的患者更為常見,此種損害特點(diǎn)為延遲發(fā)生、進(jìn)行性加重、不可逆的聽力下降,而目前尚無有效的預(yù)防及治療方法[3]。因此,在放療患者中對內(nèi)耳損傷的保護(hù)就顯得尤為重要。隨著放療物理和放射生物的進(jìn)展,調(diào)強(qiáng)放療已成為鼻咽癌的標(biāo)準(zhǔn)放療技術(shù),放療計劃制定和實施中對內(nèi)耳進(jìn)行劑量限值成為可能。我們擬通過對骨導(dǎo)4K Hz電測聽值作相關(guān)回顧性分析,了解鼻咽癌IMRT技術(shù)中化療患者年齡、劑量等因素對SNHL發(fā)生率的影響,并嘗試尋找耳蝸放療劑量限定值,提供放療計劃制定中耳蝸劑量限值參考。 材料與方法 共有2009-2011年中29例(58耳)放化療方案完全一致的病例進(jìn)入此項研究。所有病例均為病理證實的初治鼻咽癌,行IMRT放射治療和PF方案化療。所有病例年齡≤55歲(以減少老年性SNHL對聽力測試結(jié)果的影響),放療前聽力水平均正常(檢測顯示為正常電測聽),在隨訪時均無腫瘤局部和區(qū)域復(fù)發(fā)及全身轉(zhuǎn)移,有完整的體檢記錄及聽力學(xué)檢測資料包括耳鼓膜描述、電測聽、聲阻抗測試。入組時,我們排除放療前后聲阻抗鼓室圖為B型的分泌性中耳炎患者(中耳積液有可能影響骨導(dǎo)測聽值)。放療前、放療結(jié)束、放療后3個月、放療后6個月、放療后1年、放療后2年均隨訪電測聽和聲阻抗的情況,入組患者截止時點(diǎn)至少為放療后12個月。以骨導(dǎo)4K Hz電測聽值(閾值增大≥lOdB認(rèn)為有意義)作相關(guān)線性回歸分析、logistic分析和odds ratio分析,分析放射性內(nèi)耳損傷相關(guān)因素,確定內(nèi)耳劑量限定值。 結(jié)果 58耳符合電測聽分析條件,放療后25.8%耳惡化。1.多元線性回歸分析發(fā)現(xiàn)：放療劑量(p=0.01,評估值0.46)、年齡(p=0.002,評估值0.47)均與SNHL發(fā)病率有統(tǒng)計學(xué)上的相關(guān)性。2.1ogistic回歸分析發(fā)現(xiàn)：放療劑量(p=0.02,評估值0.76)、年齡(p=0.005,評估值0.14)均與SNHL發(fā)病率有統(tǒng)計學(xué)上的相關(guān)性。3.OddsRatio分析發(fā)現(xiàn)：劑量評估值為1.001,年齡評估值為1.151,兩者均是SNHL發(fā)病率的危險因素。4.對劑量與放療后SNHL的發(fā)生率相關(guān)性的研究發(fā)現(xiàn)：良好組和惡化組之間劑量比較差異有統(tǒng)計學(xué)上的意義(良好組劑量36.87Gy,惡化組劑量39.43Gy,P=0.0492),我們推薦在放射治療計劃制定中耳蝸劑量應(yīng)限值在37Gy以下。 結(jié)論 鼻咽癌IMRT技術(shù)下的放化療患者,無論是線性回歸模型、logstic回歸模型還是Odds Ratio分析得出的結(jié)論一致。耳蝸照射劑量、年齡都與放療后SNHL的發(fā)生率具有統(tǒng)計學(xué)上的相關(guān)性。為了預(yù)防IMRT技術(shù)下鼻咽癌放化療患者SNHL的發(fā)生,推薦劑量值保持在37Gy以下。 背景和目的 我們的前期研究顯示,鼻咽癌放化療患者耳蝸放射劑量限制在37Gy可以預(yù)防SNHL的發(fā)生。以往研究報道,當(dāng)耳蝸劑量達(dá)41-50Gy時,SNHL的發(fā)病率達(dá)31%,60-90Gy時更高達(dá)62%[4]。為保證鼻咽部腫瘤靶區(qū)的劑量,耳蝸劑量限定值以47Gy為宜[5],過低劑量限值可能影響腫瘤靶區(qū)劑量。因此,有必要尋找更多的內(nèi)耳放射損傷保護(hù)方法。 黑色素廣泛分布于哺乳動物包括人的內(nèi)耳中,如前庭暗細(xì)胞區(qū)、耳蝸血管紋、內(nèi)淋巴囊等處的黑素細(xì)胞中[6]。大量文獻(xiàn)證實,黑色素在噪音損傷、耳毒性藥物和老年性耳聾中均有保護(hù)作用[7.8]。由于黑色素具有螯合金屬陽離子的能力、氧化自由基清除能力,能量儲存和轉(zhuǎn)化能力[9],可能對耳蝸放射性損傷具有保護(hù)作用,但迄今為止尚未見相關(guān)報導(dǎo)。現(xiàn)有研究表明：雜色動物前庭、耳蝸和內(nèi)淋巴囊內(nèi)均有酪氨酸酶活性表達(dá),因此雜色動物內(nèi)耳黑素細(xì)胞能主動合成黑色素。白化動物則由于酪氨酸酶的遺傳性缺陷,體內(nèi)不能合成黑色素,因此白化動物內(nèi)耳黑素細(xì)胞中沒有黑色素分布[10]。由于白化和雜色豚鼠的內(nèi)耳存在著上述差異,因此可以利用白化和雜色豚鼠相對比來研究黑色素在內(nèi)耳中的功能。我們擬建造10Gy、15Gy、20Gy的豚鼠內(nèi)耳損傷照射模型,然后通過比較兩種豚鼠在三種劑量梯度下,在24小時和2周這兩個時間截點(diǎn)上內(nèi)耳損傷的差異,來探討黑色素在放射性內(nèi)耳損傷中是否具有保護(hù)作用。 材料和方法 將56只豚鼠分為雜色組和白化組,分別給予不照光、1000cGy、1500cGy、2000cGy照射,于照射后24小時和照射后2周斷頭處死,進(jìn)行耳蝸鋪片和制作冰凍切片,觀察毛細(xì)胞、血管紋和螺旋韌帶的損傷情況。1.選取第三回耳蝸基底膜進(jìn)行耳蝸鋪片,四氮唑藍(lán)染色,鏡下觀察毛細(xì)胞排列情況,并進(jìn)行細(xì)胞計數(shù),計算缺失率。2.常規(guī)冰凍切片,HE染色,計量第三回血管紋的厚度,細(xì)胞密度,毛細(xì)血管數(shù)和螺旋韌帶厚度及細(xì)胞密度。3.結(jié)果進(jìn)行相關(guān)統(tǒng)計分析。 研究結(jié)果 在放射性內(nèi)耳損傷模型中,研究結(jié)果如下：1.黑色素：白化組無論照射與否,均未見黑色素；雜色組隨著照射劑量增加和照射后時間延長,黑色素有遞增趨勢,照射后2周黑色素增加更明顯。2.毛細(xì)胞狀況：隨著照射時間延長和照射劑量的增加,兩組豚鼠毛細(xì)胞紊亂和缺失率都有增加,但在同等劑量和時間條件下,白化組比雜色組排列更紊亂,缺失率更高。3.血管紋狀況：隨著照射劑量增加和照射后時間延長,白化組血管紋厚度減少,而雜色組基本不變,甚至有增厚趨勢；照射后24小時,血管紋細(xì)胞數(shù)計數(shù)差別不明顯。照射后2周,無論白化組還是雜色組,有核細(xì)胞都減少,白化組比雜色組減少更明顯。4.毛細(xì)血管狀況：照射后,兩組豚鼠毛細(xì)血管數(shù)都增加,但兩組之間差異不明顯。5.螺旋韌帶狀況：隨著照射劑量增加和照射后時間延長,兩組豚鼠螺旋韌帶纖維細(xì)胞均有減少的趨勢,白化組比雜色組更明顯。 結(jié)論 內(nèi)耳黑色素量與內(nèi)耳血管紋細(xì)胞、螺旋韌帶細(xì)胞及基底膜毛細(xì)胞損傷變化呈負(fù)相關(guān),此種相關(guān)性在照射后2周比照射后24小時更明顯,但黑色素與血管紋微循環(huán)關(guān)系不明顯。 在放射性內(nèi)耳損傷中,內(nèi)耳黑色素與放射后SNHL的發(fā)生可能具有相關(guān)性,值得進(jìn)一步研究。
[Abstract]:Clinical analysis of radiation induced inner ear injury in patients with nasopharyngeal carcinoma undergoing IMRT chemotherapy
Background and purpose
Radiotherapy is the most effective treatment for nasopharyngeal carcinoma in China. At the same time, radiation therapy is one of the main treatment methods for other head and neck malignant tumors, [1].. In recent years, the survival rate of five years after the treatment of head and neck tumor has been obviously improved, but the consequent long-term side effects are becoming more and more recognized. The second [2]. radiotherapy (Sensori-neural hearing loss, SNHL) after radiotherapy is a common sequelae after radiotherapy for nasopharyngeal carcinoma, especially in patients with combined chemotherapy, which is characterized by delayed onset, progressive weight, and irreversible hearing loss, but there is no effective preconditioning at present. As a result, the protection of the internal ear injury in patients with radiotherapy is particularly important. With the progress of Radiotherapy Physics and radiation biology, intensity modulated radiation therapy has become a standard radiotherapy technique for nasopharyngeal carcinoma. It is possible to limit the dose of the inner ear in the formulation and implementation of the radiotherapy plan. We intend to use the electrical audiometry value of 4K Hz for bone conduction. A retrospective analysis was made to understand the effect of age and dose on the incidence of SNHL in patients with nasopharyngeal carcinoma (IMRT), and to try to find the dose limited value of the cochlear radiotherapy, and to provide the radiotherapy plan for the reference of the dose limit of the cochlea.
Materials and methods
In a total of 2009-2011 years, 29 cases (58 ears) were fully matched to the study. All cases were confirmed by the pathology of nasopharyngeal carcinoma, IMRT radiotherapy and PF regimen chemotherapy. All cases were less than 55 years old (to reduce the effect of aging SNHL on hearing test results). The hearing levels before radiotherapy were normal (detection and display) For normal electrical audiometry, there were no local and regional recurrence and systemic metastases at the follow-up. Complete physical examination records and audiological data included the ear drum membrane description, electrical audiometry, and acoustic impedance test. When we entered the group, we excluded the acoustic impedance tympane of B type secretory otitis media before and after radiotherapy (the middle ear effusion may affect bone conduction. " 3 months after radiotherapy, 3 months after radiotherapy, 6 months after radiotherapy, 1 years after radiotherapy, 2 years after radiotherapy, and at least 12 months after radiotherapy at 2 years. Correlation linear regression analysis, logistic analysis and odds r were made with bone guided 4K Hz audiometric value (threshold value greater than lOdB) Atio analysis, analysis of factors related to radiation inner ear injury, determine the dose limit of inner ear.
Result
The 58 ears were in accordance with the conditions of electrical audiometry, and the 25.8% ear worsening.1. multivariate linear regression analysis after radiotherapy found that the dose of radiotherapy (p=0.01, evaluation value 0.46), age (p=0.002, evaluation value 0.47) were all statistically correlated with the incidence of SNHL,.2.1ogistic regression analysis was found: dosage (p=0.02, evaluation value 0.76), age (p=0.005, evaluation value 0.14). A statistically significant correlation with the incidence of SNHL was found in.3.OddsRatio analysis: the dose assessment was 1.001 and the age assessment was 1.151. Both were the risk factors for the incidence of SNHL. The correlation between the dose and the incidence of SNHL after radiotherapy was found to be statistically significant in the dose comparison between the good group and the worsening group. The best dose is 36.87Gy, the dose of deterioration group is 39.43Gy, P=0.0492). We recommend that the cochlear dose limit should be below 37Gy in the formulation of radiotherapy plan.
conclusion
Patients with nasopharyngeal carcinoma (nasopharyngeal carcinoma) with IMRT technique are consistent with the results of linear regression model, logstic regression model or Odds Ratio analysis. The dose of cochlear irradiation and age are statistically related to the incidence of SNHL after radiotherapy. In order to prevent the occurrence of SNHL in patients with nasopharyngeal cancer chemoradiotherapy under IMRT Technology, the recommended dose values are recommended. Keep it below 37Gy.
Background and purpose
Our previous study showed that the dose limit of the cochlear radiation dose to 37Gy in patients with nasopharyngeal carcinoma could prevent the occurrence of SNHL. In the previous study, when the cochlear dose reached 41-50Gy, the incidence of SNHL was 31%, and 62%[4]. was more than 62%[4]. to ensure the dose of the target area of the nasopharyngeal tumor. The cochlear dose limited value was [5] with 47Gy as appropriate, and the low dose limit was limited. The value may affect the dose of tumor target area. Therefore, it is necessary to find more protection methods for radiation injury of inner ear.
Melanin is widely distributed in mammals including human inner ears, such as the vestibule dark cell areas, the cochlear veins, and the endolymphatic sac, which are widely documented in [6].. Melanin is protected by noise damage, ototoxic drugs and senile deafness, the ability of [7.8]. to be oxidized by melanin with chelating metal cations. Free radical scavenging ability, energy storage and transformation capacity [9] may have protective effects on the cochlear radiation damage, but so far no related reports have been reported. The present study shows that tyrosinase activity is expressed in the vestibule, cochlea and endolymphatic sac of the colored animals. Therefore, melanin cells in the clutter animal can be active in synthesizing melanin. Because of the genetic defects of tyrosinase and the inability of the body to synthesize melanin, the non melanin distribution in the melanocytes of albino melanocytes in the albino animal's inner ear [10]. has the above differences due to the albino and the inner ear of the variegated guinea pigs. Therefore, the function of melanin in the inner ear can be studied by the contrast of albino and variegated guinea pigs. In order to explore the protective effect of melanin on the inner ear injury of radioactive inner ear by comparing the damage of the inner ear of the two guinea pigs at the 24 and 2 weeks at the 24 and 2 weeks, the internal ear injury model of 10Gy, 15Gy and 20Gy was built.
Materials and methods
56 guinea pigs were divided into the color group and the albino group. They were irradiated with no light, 1000cGy, 1500cGy, 2000cGy, 24 hours after irradiation and 2 weeks after irradiation. The cochlear slices and frozen sections were made to observe the damage of the hair cells, vascular lines and spiral ligaments. The third cochlear basement membrane was selected for the cochlear tablet and tetrazolium. Blue staining, observed the arrangement of hair cells under the microscope, and counted the cells, calculated the loss rate.2. conventional frozen section, HE staining, measured the thickness of third blood vessels, cell density, the number of capillary and the thickness of spiral ligament and cell density.3. results.
Research results
In the radiation injury model of inner ear, the results are as follows: 1. melanin: no matter the irradiation or not, no melanin is found in the albino group. With the increase of irradiation dose and the prolongation of the time after irradiation, the melanin has a tendency to increase. The increase of melanin in the 2 weeks after irradiation is more obvious.2. capillary cell condition: with the prolongation of the irradiation time and the dose of irradiation. In addition, the hair cell disorder and loss rate of the two groups of guinea pigs increased, but in the same dose and time condition, the albino group was more disorder than the color group, and the loss rate was higher than that of the.3.. With the increase of irradiation dose and the prolongation of the irradiation time, the vascular thickness of the albino group decreased, and the color group was basically unchanged, even thickening trend. At 24 hours after irradiation, the number of vascular cell counts was not significant. At 2 weeks after irradiation, the nucleated cells decreased and the whitening group decreased more obvious.4. capillary conditions than the color group. After irradiation, the number of capillaries in the two groups of guinea pigs increased, but the difference between the two groups was not evident in the.5. spiral ligament condition: with the illumination. After the increase of radiation dose and prolonged irradiation time, the two groups of guinea pig spiral ligament fibroblasts showed a decreasing trend, and the albino group was more obvious than the color group.
conclusion
The amount of melanin in the inner ear was negatively correlated with the damage and changes of the inner ear vascular cells, the spiral ligament cells and the basal membrane hair cells. This correlation was more obvious at 2 weeks after irradiation than the 24 hours after irradiation, but the relationship between melanin and vascular microcirculation was not obvious.
In the radiation inner ear injury, melanin in the inner ear may be related to the occurrence of SNHL after radiation. It is worth further studying.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R764

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